MRI is a powerful, non-invasive diagnostic tool for living organisms and provides real-time images with great spatial resolution (Terreno et al., (2010) Chemical Reviews 110: 3019-3042). The image contrast is based on the excitation and relaxation of water and lipids in tissues. The intrinsic longitudinal (T1) and transverse (T2) relaxation time of different parts of the tissues generate image contrast based on the MR signal intensity. Because of the small intrinsic variations in T1 and T2 of most tissues, contrast agents are routinely applied to enhance contrast by shortening the relaxation time of the protons in the neighboring water molecules (Strijkers et al., (2007) Anti-cancer Agents in Medical Chemistry 7; Waters et al., (2008) Basic Res. Cardiol. 103: 114-121; Yoo & Pagel (2008) Frontiers in Bioscience 13: 1733-1752; Na et al., (2009) Advanced Materials 21: 2133-2148). T1 positive contrast agents mainly shorten the relaxation time T1, generating a brighter image, while T2 contrast agents produce a darker image by shortening the transverse relaxation time, T2.
The effectiveness of a contrast agent is usually evaluated by its relaxivity r1 or r2, given by: 1/Tisample=1/Tisolvent+ri[M](i=1, 2). In this equation, 1/Tisample and 1/Tisolvent are the relaxation rates of the sample and pure solvent in s−1, respectively, and [M] is the concentration of the contrast agent in mM. The ratio between r2 and r1 (r2/r1) is generally used to determine whether a contrast agent is suitable for T1 or T2 contrast (Strijkers et al., (2007) Anti-cancer Agents in Medical Chemistry 7). Normally, T1 contrast agents have a lower (r2/r1) ratio (e.g., 1-2) while T2 contrast agents have a larger (r2/r1) ratio (>10) (Tromsdorf et al., (2009) Nano Letts. 9: 4434-4440). T1 positive contrast agents are clinically preferred because the brighter contrast brings higher resolution and is more easily detected in the MR images (Okuhata et al., (1999) Advanced Drug Delivery Reviews 37: 121-137).
T1 contrast agents are generally paramagnetic Gd3+ or Mn2+ complexes (Caravan et al., (1999) Chemical Reviews 99: 2293-2352; Federle et al., (2000) J. Magnetic Resonance Imaging 12: 689-701). Their small sizes allow them to freely diffuse into extravascular space with low specificity (Caravan, P (2006) Chem. Soc. Revs 35: 512-523). Conjugation to macromolecules, such as dendrimers, (Cheng et al., (20090 Adv. Functional Materials 19: 3753-3759; Swanson et al., (2008) Int. J. Nanomed. 3: 201-210), liposomes (Ghaghada et al., (2008) Academic Radiol. 15: 1259-1263; Fossheim et al., (1999) Magnetic Resonance Imaging 17: 83-89; Zhang et al., (2009) Europ. J. Radiol. 70: 180-189), or proteins (Caravan, P. (2009) Accounts of Chemical Res. 42: 851-862; Yang et al., (2008) J. Am. Chem. Soc. 2008, 130: 9260-9267) has been explored to enhance the relaxivity and minimize the diffusion. Recently, MnO18 and Gd2O3 (Park et al., (2009) Acs Nano 3: 3663-3669) nanoparticless have been developed as T1 contrast agents (Na & Hyeon (2009) J. Mat. Chem. 19: 6267-6273). Unfortunately, the relaxivity of MnO nanoparticles is very low and Gd3+-containing agents pose a long-term toxicity risk (Hasebroock & Serkova (2009) Expert Opinion Drug Metab. Toxicol. 5: 403-416). Continuing efforts are still needed to identify safer T1 contrast agents. (Terreno et al., (2010) Chemical Reviews 110: 3019-3042; Schwert et al., (2002) Contrast Agents I 221: 165-199).
Superparamagnetic iron oxide nanoparticles (NPs) have been the primary choice for T2 contrast agents (Chu, G., (1994) J. Biol. Chem. 269: 787-790). They are generally believed to be safe and can be potentially reabsorbed through normal iron metabolic pathways (Weissleder et al., (1989) Am. J. Roentgenol. 152: 167-173; Stark et al., (1988) Radiol. 168: 297-301). Several types of iron oxide NPs have been developed for imaging liver, spleen, vascular compartments, and lymph nodes (Corot et al., (2006) Adv. Drug Delivery Revs. 58: 1471-1504) including clinically-approved FERIDEX™ ((2006) Drug News & Perspectives 7: 422-422) and RESOVIST™ (Reimer et al., (2003) European Radiol. 13: 1266-1276).
Because of the safer nature of iron oxide NPs and their intrinsic ma§netism, there has been initial interest in exploring their potential as T1 contrast agents (Tromsdorf et al., (2009) Nano Letts. 9: 4434-4440; Federle et al., (2000) J. Magnetic Resonance Imaging 12: 689-701; Taboada et al., (2007) Langmuir 23: 4583-4588). The reported strategy was to decrease the size of iron oxide NPs to less than 5 nm. The s/v ratio of a spherical NP scales with 3/radius (e.g., 1.5 nm−1 for a 4 nm NP and 0.5 nm−1 for a 12 nm NP) and the fraction of surface atoms increases significantly (e.g., 40% for a 4 nm NP), as the NP size decreases. The surface atoms of NPs are normally coordinated by capping ligands. The complexation between the capping ligands and surface atoms forms a paramagnetic layer, which results in mixed paramagnetic and superparamagnetic behaviors in small NPs (Guardia et al., (2007) J. Magnetism Magnetic Mats 316: E756-E759). These small sized NPs show a much lower magnetization, and consequently decreased effects on the T2 relaxation. Examples include 4 nm iron oxide NPs with a r2/r1 ratio as low as 2.4 at 1.4 Tesla (T) (Tromsdorf et al., (2009) Nano Letts. 9: 4434-4440), 1.3 nm ultra-small iron oxide NPs with a 1.6 r2/r1 ratio at 5 T, and 5 nm Fe2O3-citrate solution with a r2/r1 ratio of 2.46 at 20 MHz (Taboada et al., (2007) Langmuir 23: 4583-4588; Cho et al., (2006) Nanotechnology 17: 640-644). These lower r2/r1 ratios suggest that these NPs can be potentially used as T1 contrast agents. However, when the NP size gets too small, the aggregation issue becomes critical (Tromsdorf et al., (2009) Nano Letts. 9: 4434-4440). In addition, small NPs (<8 nm) tend to experience fast renal clearance and escape from blood circulation (Longmire et al., (2008) Nanomedicine 3: 703-717). Therefore, it is important to examine other characteristics, such as surface coatings (LaConte et al., (2007) J. Magnetic Resonance Imaging 26: 1634-1641; Qin et al., (2007) Advanced Materials 19: 1874) and shapes (Joshi et al., (2009) J. Physical Chem. 113: 17761-17767; Park et al., (2008) Advanced Materials 20: 1630) which also affect the magnetic properties and T2 relaxation.
Anisotropic nanostructures have attracted much attention in various applications because of their unique electronic, magnetic, and optical properties (Cohen-Karni et al., (2010) Nano Lett. 10: 1098-1102; Chen et al., (2007) Langmuir 23: 4120-4129;). In particular, the synthesis of one-dimensional (1D) metallic and semiconductor nanostructures has been well documented (Baker et al., (2010) Nano Lett. 10: 195-201; Xia et al., (2009) Angew. Chem. Int. Ed. 48: 60-103; Lee et al., (2007) J. Am. Chem. Soc. 129: 10634-10635). Most recently, ultrathin (approximately 2 nm) nanowires (Cademartiri & Ozin (2009) Adv. Mater. 21: 1013-1020), such as Au (Li et al., (2008) Nano Lett. 8: 3052-3055; Wang & Sun (2009) Chem.-an Asian J. 4, 1028-1034; Poudyal et al., (2008) Nanotechnology 19: 355601-1-4; Huo et al., (2008) Nano Lett. 8: 2041-2044), FePt (Chen et al., (2007) J. Am. Chem. Soc. 129: 6348-6349), and oxides (Huo et al., (2009) Nano Lett. 9, 1260-1264; Yu et al., (2006) J. Am. Chem. Soc. 128: 1786-1787), have attracted much interest. In contrast, only few studies of ultrathin iron oxide magnetic nanoparticles have been reported (e.g., iron oxide nanobars and nanowires (Wang & Yang (2009) Chem. Eng. J. 147: 71-78). Spherical iron oxide nanoparticles have been primarily explored in targeted drug delivery, localized therapy, or as contrast agents for magnetic resonance imaging (MRI) (Pankhurst et al., (2003) J. Phys. D-Appl. Phys. 36: R167-R181; Veiseh et al., (2010) Adv. Drug Deliv. Rev. 62: 284-304). A recent study of ultrathin iron oxide nanoworms showed long blood circulation time, enhanced retention at tumor sites, and improved targeting efficiency (Park et al., (2008) J. Adv. Mater. 20: 1630-1635), which suggests that anisotropic iron oxide nanoparticles could potentially lead to further advancement in biomedical applications.
The synthetic approach to iron oxide spheres has been intensively focused on the thermal decomposition of iron (III) oleate complexes, due to its great reproducibility and control of the physical parameters (Park et al., (2004) Nat. Mater. 3: 891-895). In this method, the Fe(III) oleate precursor is typically heated up to over 300° C., producing different-sized spherical nanoparticles with a narrow size distribution. Cubic and bipyramid-shaped particles were also reported using this method as a result of the selective absorption of impurity ions, such as Cl−, Na+, or oleate (Shavel et al., (2007) Adv. Funct. Mater. 17: 3870-3876; Shavel et al., (2009) Chem. Mater. 21: 1326-1332; Shavel & Liz-Marzan (2009) Phys. Chem. Chem. Phys. 11: 3762-3766; Hai et al., (2010) Colloid Interface Sci. 346: 37-42; Kovalenko et al., (2007) J. Am. Chem. Soc. 129: 6352-6353; Xu et al., (2010) Nanoscale 2: 1027-1032; Kim et al., (2007) J. Am. Chem. Soc. 129: 5812-5813).
Even though the decomposition of the iron oleate complex is widely used for the synthesis of iron oxide nanoparticles, few mechanistic studies are available to understand the growth process. Hyeon (Kwon et al., (2007) J. Am. Chem. Soc. 129: 12571-12584) proposed that the dissociation of the first oleate ligand at around 200-240° C. triggered the nucleation event, followed by nanoparticle growth through the decomposition of the two remaining ligands above 300° C. However, it has been rather difficult to conclusively confirm the dissociation process of the iron oleate complex. A recent density functional theory (DFT) electronic structure calculation of iron carboxylate complexes showed different dissociation temperatures of the three carboxylate ligands (Lopez-Cruz & Lopez (2009) Mol. Phys. 107: 1799-1804. The first and the second ligands have similar dissociation temperatures, while the dissociation temperature of the third ligand was significantly higher. The calculations further proposed the formation of an Fe—O bond between the third ligand and the iron center. Unfortunately, an understanding of the chemical microenvironments of these three ligands and their effects on the nanostructure formation is still lacking.